Interleukin 33 (IL-33), also known as nuclear factor (NF) in high endothelial venules (NF-HEV), is a cytokine belonging to the IL-1 superfamily. IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines. IL-33 mediates its biological effects by interacting with the receptors ST2 (also known as IL1RL1) and IL-1 Receptor Accessory Protein (IL1RAP) to activate intracellular molecules in the NF-κB and MAP kinase signaling pathways that drive production of type 2 cytokines (e.g., IL-4, IL-5, and IL-13) from polarized helper T cells (Th2) and Group-2 innate lymphoid cells (ILC2) in the skin, lungs, and gastrointestinal tract. IL-33 acts directly on mast cells to trigger their activation, and stimulates eosinophils and basophils to degranulate, causing tissue damage. The induction of type 2 cytokines by IL-33 in vivo is believed to induce the severe pathological changes observed in mucosal organs following administration of IL-33 (see, e.g., Schmitz et al., Immunity, 23(5): 479-490 (2005); and Chackerian et al., J. Immunol., 179 (4): 2551-2555 (2007))
Both the in vivo expression profile of IL-33 and its cellular targets suggest a role for IL-33 in Th2-driven pathologies. For example, IL-33 expression has been detected in inflamed tissue from patients with moderate-to-severe asthma, atopic dermatitis, allergic rhinitis, food allergies, rheumatoid arthritis, multiple sclerosis, and Crohn's disease. In addition, functional single nucleotide polymorphisms (SNPs) in the distal promoter region of ST2 (IL-33R) have shown a significant association with atopic dermatitis (see, e.g., Shimizu et al., Hum. Mol. Genet., 14(19): 2919-2927 (2005)). Genome-wide association studies (GWAS) have also shown a strong link with SNPs in IL-33 and ST2 (IL-33R) genes for asthma in multiple studies of ethnically diverse groups (see, e.g., Gudbjartsson et al., Nat. Genet., 41(3): 342-347 (2009); Melén et al., J Allergy Clin. Immunol., 126(3): 631-637 (2010); Moffatt et al., New Engl J. Med., 363(13):1211-1221 (2010); and Torgerson et al., Nat. Genet., 43(9): 887-92 (2011)). IL-33 (possibly in combination with IL-25 and TSLP) also activates innate lymphoid cells (ILC2 cells) leading to Th2 cytokine secretion, anti-parasitic responses, and tissue immunopathology.
Studies also suggest that IL-33 plays a direct role in some cancers expressing the IL-33 receptor such as, for example, epithelial cancers (i.e., carcinomas) by acting as a survival or growth factor for cancer cells. Such responsiveness to IL-33 might contribute to escape of certain cancer cell types from current standard of care (e.g., chronic myelogenous leukemia (CML), breast cancers, and gastrointestinal cancers). Furthermore, IL-33 may play an indirect role in cancer progression by reducing the protective activity of the immune system in controlling tumor cells. Other recent studies suggest that IL-33 plays a role in the pathology of fibrosis, such as, for example, skin fibrosis, liver fibrosis, systemic sclerosis, and lung fibrosis. In addition, Mchedlidze et al., Immunity, 39: 357-371 (2013), demonstrates that hepatic expression of interleukin-33 (IL-33) is both required and sufficient for severe hepatic fibrosis in vivo.
Therefore, there is a need for inhibitors of IL-33 (e.g., antibodies) that bind IL-33 with high affinity and effectively neutralize IL-33 activity. The invention provides an IL-33 binding agent that binds to and inhibits IL-33.